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• Author's response to e-letter "Therapeutic strategy of Malignant glioma and the fetal-maternal wellbeing”
  Valeria Filippi
  Published on: 3 June 2021
• Therapeutic strategy of Malignant glioma and the fetal-maternal wellbeing
  Kotoe Kamata, Takashi Maruyama, Risa Fukushima and Makoto Ozaki
  Published on: 24 April 2021

• Published on: 3 June 2021

  Author's response to e-letter "Therapeutic strategy of Malignant glioma and the fetal-maternal wellbeing”

  • Valeria Filippi, Resident of the Department of Gynaecology and Obstetrics University Hospital Basel

  Thank you very much for your letter on our published case report of a pregnant woman that was diagnosed with a left parietal glioma in the 28^th gestational week after a first generalised seizure, and for your opinion and thorough review of the literature.

  In our patient we performed a two-stage approach with first a tumour resection under general anaesthesia and preservation of the pregnancy and after caesarean section performed in the 37^th gestational week an awake craniotomy for resection of residual tumour under neuropsychological monitoring and mapping.

  We decided to do a two-stage approach after a round table where obstetricians, neurosurgeons, anesthetists, neonatologists, and midwives were involved and after several long conversations with the patient and her husband. For the patient clearly the health of her unborn child was the most important aspect of her treatment and therefore she wanted to prolong the pregnancy until term. The tumor of our patient was located with a broad base to the surface and seemed to have a plane to the underlying white matter. There was no, in this location possible eloquent, unaffected cortex overlying the tumor. Moreover, our patient was already in the 28^th gestational week of her pregnancy, the uterine fundus was high and the abdomen extended. The use of cortical or subcortical electric stimulation does increase the seizure risk^1-4. Because of all these reasons we decided aga...

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  Thank you very much for your letter on our published case report of a pregnant woman that was diagnosed with a left parietal glioma in the 28^th gestational week after a first generalised seizure, and for your opinion and thorough review of the literature.

  In our patient we performed a two-stage approach with first a tumour resection under general anaesthesia and preservation of the pregnancy and after caesarean section performed in the 37^th gestational week an awake craniotomy for resection of residual tumour under neuropsychological monitoring and mapping.

  We decided to do a two-stage approach after a round table where obstetricians, neurosurgeons, anesthetists, neonatologists, and midwives were involved and after several long conversations with the patient and her husband. For the patient clearly the health of her unborn child was the most important aspect of her treatment and therefore she wanted to prolong the pregnancy until term. The tumor of our patient was located with a broad base to the surface and seemed to have a plane to the underlying white matter. There was no, in this location possible eloquent, unaffected cortex overlying the tumor. Moreover, our patient was already in the 28^th gestational week of her pregnancy, the uterine fundus was high and the abdomen extended. The use of cortical or subcortical electric stimulation does increase the seizure risk^1-4. Because of all these reasons we decided against an awake craniotomy and an operation under general anesthesia was performed. During the first procedure we did not use electrophysiological monitoring or functional mapping at all to keep the seizure risk as low as possible.

  We acknowledge that there are reports in the literature emerging that awake craniotomy during pregnancy seem to be a safe and feasible option and the authors of this letter provide a well-managed example from their own experience⁵. However, their patient was having a glioma with clear high-grade features present, leaving less time for multi staged procedures as these are aggressive tumors with limited prognosis. The tumor of our patient did radiologically not have high grade features, although preoperative imaging was obtained without administration of contrast. Histology of the tumor did show diffuse IDH-mutant astrocytoma classified between WHO grade II and III. The tumor exhibited methylation of the O-6 methylguanine DNA methyltransferase (MGMT) promotor and no complete deletion of cyclin-dependent kinase inhibitor 2a/b (CDKN2a/b) that are both positive prognostic and IDH mutation is a positive predictive marker. Morphologically it did show some anaplastic features and that is why it was finally treated like an anaplastic tumor.

  5-aminolevulenic acid (5-ALA) in glioma surgery permits the intraoperative visualization of malignant glioma tissue and supports the neurosurgeon to reach a complete resection of the contrast-enhancing tumor. Some studies show a potential risk for the fetus if 5-ALA has been given together with irradiation in the first trimester⁶. To this date, there is no evidence about a possible teratogenic effect of 5-ALA in the third trimester^7-9. 

  In our clinic we do not use the drug Gliolan® but a pharmaceutic product containing 5-ALA that is completely manufactured by our hospital pharmacy. Before application of this drug in our pregnant patient we had extensive consultation with our clinical pharmacologists and pharmacists. This counseling did not identify a risk to the pregnancy of our patient who was in the third trimester and therefore application was officially allowed. Before application of this medication we had a shared decision making conversation with the patient, where we informed her openly about studies showing possible risks for the fetus in the first trimester⁶ but that there was no evidence for risk to her pregnancy in the current stage. She then agreed to the use of 5-ALA for her surgery.

  In the retrospect, we agree that administration of 5-ALA may not have been necessary since we considered a possible second operation already initially.

  The authors of the e-letter took the statement that propofol would not be appropriate from two cases described from Sethuraman et al. where after very long procedures (11 and 10 hours respectively) the use propofol caused maternal mild metabolic acidosis¹⁰.

  As our procedure did not last that long, the use of propofol during pregnancy in this case was reasonable as also confirmed by Wang et al. ¹¹      

  Furthermore, during surgery we regularly performed ABGs in order to monitor the pH and avoid acidosis.

  It will remain challenging to define standards of care for glioma patients in pregnancy. However, we agree with the authors of this letter that the single-stage strategy with awake craniotomy is a considerable alternative to our proposed strategy and that multidisciplinary discussion and careful perioperative planning are of upmost importance for these patients.                                                                                                  

   

  1.           Jasper H. Electrocorticography. In. Boston: Little Brown1954:p. 692 - 738.

  2.           Blume WT, Jones DC, Pathak P. Properties of after-discharges from cortical electrical stimulation in focal epilepsies. Clin Neurophysiol. 2004;115(4):982-989.

  3.           Karakis I, Leeman-Markowski BA, Leveroni CL, et al. Intra-stimulation discharges: an overlooked cortical electrographic entity triggered by direct electrical stimulation. Clin Neurophysiol. 2015;126(5):882-888.

  4.           PINSKY C, BURNS BD. Production of epileptiform afterdischarges in cat's cerebral cortex. J Neurophysiol. 1962;25:359-379.

  5.           Kamata K, Fukushima R, Nomura M, Ozaki M. A case of left frontal high-grade glioma diagnosed during pregnancy. JA Clin Rep. 2017;3(1):18.

  6.           Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392-401.

  7.           Hadjipanayis CG, Widhalm G, Stummer W. What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas? Neurosurgery. 2015;77(5):663-673.

  8.           Yang JZ, Van Vugt DA, Melchior MF, Hahn PM, Reid RL. Photodynamic ablation of early pregnancy in the rat with 5-aminolevulinic acid: a potential new therapy for tubal ectopic pregnancy in the human. Fertil Steril. 1994;62(5):1060-1065.

  9.           Olzowy B, Hundt CS, Stocker S, Bise K, Reulen HJ, Stummer W. Photoirradiation therapy of experimental malignant glioma with 5-aminolevulinic acid. J Neurosurg. 2002;97(4):970-976.

  10.        Sethuraman M, Neema PK, Rathod RC. Prolonged propofol infusion in pregnant neurosurgical patients. J Neurosurg Anesthesiol. 2007;19:67-8.

  11.        Wang, Lars Peter MD (Cph), FANZCA*; Paech, Michael James MBBS, DRCOG, FRCA, FANZCA, FFPMANZCA, FRANZCOG (Hon), DM† Neuroanesthesia for the Pregnant Woman, Anesthesia & Analgesia: July 2008 - Volume 107 - Issue 1 - p 193-200

   

   

   

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  Conflict of Interest:
  None declared.

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• Published on: 24 April 2021

  Therapeutic strategy of Malignant glioma and the fetal-maternal wellbeing

  • Kotoe Kamata, Assistant professor of Anesthesiology Tohoku University School of Medicine
  • Other Contributors:
    • Takashi Maruyama, Lecturer of Neurosurgery
    • Risa Fukushima, Assistant professor of Anesthesiology
    • Makoto Ozaki, Director of Primary Care Medicine

  Dear Dr. Biswas,
  In their recent article ‘Anaplastic astrocytoma during pregnancy: the importance of an effective multidisciplinary approach’, Filippi and colleagues described the therapeutic strategy for a pregnant patient whose left parietal glioma was discovered after a new-onset generalized seizure [1]. Following the multidisciplinary conference, they planned to attain a full-term pregnancy with staged tumor resection. First, the mass reduction was performed with neuronavigation and fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) under general anesthesia. Then awake craniotomy was planned for the residual tumor removal after delivery. Although the authors have provided excellent perioperative care for this complicated case, we have some reservations about the therapeutic strategy for malignant glioma in a pregnant patient.
  The guidelines for the diagnosis and treatment of gliomas, released by the European Association for Neuro-Oncology, present the following management options for newly diagnosed malignant glioma: resection or biopsy, followed by radiotherapy or chemotherapy (or combined modality treatment) [2]. In pregnant patients, the neurosurgical intervention for a malignant tumor is recommended regardless of gestational age, although the 32 week gestation point is generally used as the cutoff [3]. The extent of glioma resection is a decisive prognosis factor irrespective of tumor subtype [4]. In view of the absence of information on th...

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  Dear Dr. Biswas,
  In their recent article ‘Anaplastic astrocytoma during pregnancy: the importance of an effective multidisciplinary approach’, Filippi and colleagues described the therapeutic strategy for a pregnant patient whose left parietal glioma was discovered after a new-onset generalized seizure [1]. Following the multidisciplinary conference, they planned to attain a full-term pregnancy with staged tumor resection. First, the mass reduction was performed with neuronavigation and fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) under general anesthesia. Then awake craniotomy was planned for the residual tumor removal after delivery. Although the authors have provided excellent perioperative care for this complicated case, we have some reservations about the therapeutic strategy for malignant glioma in a pregnant patient.
  The guidelines for the diagnosis and treatment of gliomas, released by the European Association for Neuro-Oncology, present the following management options for newly diagnosed malignant glioma: resection or biopsy, followed by radiotherapy or chemotherapy (or combined modality treatment) [2]. In pregnant patients, the neurosurgical intervention for a malignant tumor is recommended regardless of gestational age, although the 32 week gestation point is generally used as the cutoff [3]. The extent of glioma resection is a decisive prognosis factor irrespective of tumor subtype [4]. In view of the absence of information on the long-term effects on newborns of mothers that received anticonvulsants, chemotherapeutics, or radiation during pregnancy [5], the fact that the patient could be safely monitored without the need for adjuvant therapies is commendable [4].
  The surgical strategy for eloquent malignant glioma in a pregnant patient offers two options. One is the two-staged strategy, as Filippi and colleagues presented, and the other is a single-stage operation with awake craniotomy in order to achieve maximum tumor resection with minimum postoperative neurological deficits. While awake craniotomy in pregnant patients is still challenging, several reports show that extensive resection with neurological monitoring is the best way to preserve the patient's motor and speech function [6-7]. Compared with the tumor removal under general anesthesia, awake craniotomy has some advantages on fetal-maternal wellbeing. The higher reliability of functional reservation is considered the most significant benefit of awake craniotomy. Especially among pregnant patients, electrophysiological monitoring and functional mapping should be minimized to reduce the risk of seizure occurrence and subsequent fetal hypoxia. As our previous case shows, the patient's subjective movement is a substitute for motor-evoked potential monitoring [7]. Maternal use of 5-ALA can be avoided in cases of awake craniotomy. In the last two decades, 5-ALA-induced fluorescence was introduced as a valuable technique for intraoperative visualization and improved resection of malignant gliomas [8]. However, its use during pregnancy is still prohibited in the European Public Assessment Report released by European Medicines Agency [9]. Fluorescence-guided surgery using 5-ALA is helpful for the identification of residual malignant glioma intraoperatively, but in the case presented by the authors, cortical or subcortical stimulation is truly informative to determine the resectable edge from the eloquent area. Considering the possible adverse reaction of 5-ALA to both the patient and fetus, fluorescence-guided surgery cannot be considered the best approach. The last concern is the detrimental effects of general anesthetics. Propofol, the most common sedative in neuroanesthesia, caused maternal mild metabolic acidosis after prolonged infusion [10]. On the other hand, volatile anesthetics have a significant tocolytic effect. Thus, awake craniotomy can reduce these unfavorable effects of general anesthesia on the patient and the fetus.
  Due to the limited evidence on the use of adjuvant therapy during pregnancy, tumors causing neurological symptoms and seizures must be treated to stabilize the maternal condition and enable a safe birth. As far as the extent of tumor resection in malignant glioma is a decisive prognosis factor, the single-stage strategy with awake craniotomy should be considered an alternative. The multidisciplinary discussion should take place within the decision-making process, and careful perioperative preparation is mandatory.

  References
  1. Filippi V, Leu SM, Marengo L, et al. Anaplastic astrocytoma during pregnancy: the importance of an effective multidisciplinary approach. BMJ Case Rep 2021;14:e242135.
  2. Weller M, van den Bent M, Hopkins K, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol 2014;15:e395-403.
  3. Lynch JC, Gouvêa F, Emmerich JC, et al. Management strategy for brain tumour diagnosed during pregnancy. Br J Neurosurg 2011;25:225-30.
  4. Nitta M, Muragaki Y, Maruyama T, et al. Proposed therapeutic strategy for adult low-grade glioma based on aggressive tumor resection. Neurosurg Focus 2015;38:E7.
  5. Zwinkels H, Dörr J, Kloet F, et al. Pregnancy in women with gliomas: a case-series and review of the literature. J Neurooncol 2013;115:293-301.
  6. Al-Mashani AM, Ali A, Chatterjee N, et al. Awake craniotomy during pregnancy. J Neurosurg Anesthesiol 2018;30:372-3..
  7. Kamata K, Fukushima R, Nomura M, et al. A case of left frontal high-grade glioma diagnosed during pregnancy. JA Clin Rep 2017;3:18.
  8. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomized controlled multicentre phase Ⅲ trial. Lancet Oncol 2006;7:392-401.
  9. European Public Assessment Report (EPAR) GLIOLAN. Available at: https://www.ema.europa.eu/en/documents/overview/gliolan-epar-summary-pub.... Accessed 20 April 2021.
  10. Sethuraman M, Neema PK, Rathod RC. Prolonged propofol infusion in pregnant neurosurgical patients. J Neurosurg Anesthesiol 2007;19:67-8.

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  Conflict of Interest:
  None declared.

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